Sleep medicine: Practice, challenges and new frontiers

Abstract

Sleep medicine is an ambitious cross-disciplinary challenge, requiring the mutual integration between complementary specialists in order to build a solid framework. Although knowledge in the sleep field is growing impressively thanks to technical and brain imaging support and through detailed clinic-epidemiologic observations, several topics are still dominated by outdated paradigms. In this review we explore the main novelties and gaps in the field of sleep medicine, assess the commonest sleep disturbances, provide advices for routine clinical practice and offer alternative insights and perspectives on the future of sleep research.

Keywords: sleep; sleep diseases; sleep disorders; sleep medicine; sleep medicine evolution.

Figure 1

Schematic representation of the “sleep train”. GABA, gamma-aminobutyrate; Ach, acetylcholine.

Figure 2

Example of a CAP sequence (CAP phases A highlighted in red) during stage N3 of NREM sleep in a patient affected by periodic limb movement disorder (PLMD). Note that the more disturbing leg movements (right part of the figure) are associated with CAP subtype A3. CAP subtypes A1 have a milder cardiovascular impact.

Figure 3

Schematic drawing of the medial brain surface with Brodmann areas. Pink: prefrontal lobe, light red: the pyramidal system (A); red: the anterior cingulate area (Br. 24, 25, 32) (B). There is a dissociation during DOA episodes between the blue fronto-dorsal cortex (in partial sleep) and the red anterior cingulate cortex (in partial wakefulness). SHE seizure onset zones of successfully operated SHE patients frequently overlap with DOA episodes' activated red anterior cingulate area.

Figure 4

Schematic representation of REM sleep circuits.

Figure 5

Schematic representation of circuits involved in the development of cataplexy. Inappropriate activation of the REM sleep atonia circuitry during wakefulness is thought to produce cataplexy. Glutamatergic REM-active SLD neurons trigger the paralysis of REM sleep via stimulation of the GABAergic/glycinergic cells in the MM. These MM neurons send inhibitory projections to skeletal motor neurons. Under normal conditions, strong positive emotions are processed via GABAergic neurons of the CeA, which then inhibit cells in the LC and vlPAG. However, in the absence of the LH hypocretinergic neurons in cataplexy, this inhibition fails, so the REM sleep atonia circuit is released from inhibition and triggers muscle paralysis while the individual remains conscious. The inhibition of LC neurons during cataplexy removes noradrenergic inputs to motoneurons, thereby enhancing the muscle paralysis of cataplexy. CeA, central nucleus of the amygdala; GABA, γ-aminobutyric acid; LC, locus coeruleus; LH, lateral hypothalamus; MM, ventral medial medulla; SubC, subcoeruleus; vlPAG, ventrolateral periaqueductal gray; MNs, motoneurons.

Figure 6

Three examples showing that value of vertical integration of high-quality EEG spectral analysis inclusive of respiration, oximetry, capnometry, and respiratory phenotype in OSA patients. (A) Patient with intrinsically high sleep quality, who develops severe sleep apnea and high loop gain, complicated by hypoventilation. Merely supporting the upper airway with continuous positive airway pressure will improve oxygenation and ventilation, but respiratory instability is likely to persist. Aggressive ventilation could amplify periodic breathing. In this case, a contribution from sleep fragmentation will be minor, given the high delta power despite the highly disruptive pathology. (B) Delta power profile is highly disrupted, and initial sleep apnea treatment is not effective. Once high loop gain is targeted (oxygen and dead space), sleep and sleep apnea markedly improves. (C) Sodium oxybate is administered (3 gm) just before lights out, but the patient remains awake for over 2 h. Once he falls asleep, the large increase in slow-wave power typical of oxybate sleep effects in not seen, but rather, sleep stage and sleep powers remain fragmented. Slow-wave power increases late, suggesting that there is substantial circadian phase delay. The drug does cause an increase in delta power while awake, before sleep onset. This fragmentation is contributed to by difficult to treat sleep apnea, and sleep fragility of uncertain cause. This patient has a diagnosis of hypersomnia in addition, being able to sleep 16+ h in a 24-h period. Even after the second dose of oxybate (3 grams), sleep remains fragmented. Stable breathing is relatively low, but there is no pervasive periodic breathing / high loop gain apnea as in the other two examples.